Multi-particulate pharmaceutical composition of quetiapine

ABSTRACT

The present invention discloses an extended release multi-particulate sprinkle composition comprising a plurality of discrete units, each discrete unit comprising quetiapine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

CROSS-REFERENCE

This application is a Continuation of U.S. application Ser. No.17/550,785, filed on Dec. 14, 2021, which is a Continuation ofInternational Application No. PCT/IB2021/058588, filed on Sep. 21, 2021,which is based on and claims priority to Indian Patent Application No.202021040886 filed on Sep. 21, 2020, the disclosures of which areincorporated by reference herein in their entireties.

FIELD OF THE INVENTION

The present invention relates to an extended release multi-particulatesprinkle composition comprising a plurality of discrete units, eachdiscrete unit comprising quetiapine or a pharmaceutically acceptablesalt thereof and one or more pharmaceutically acceptable excipients,wherein said multi-particulate composition is sprinkled onto soft foodsor edible material or liquids for oral administration.

BACKGROUND OF THE INVENTION

Quetiapine is a psychotropic agent belonging to a chemical class, thedibenzothiazepine derivatives. The chemical name of quetiapine is2-[2-(4-dibenzo[b,f][1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]-ethanol.In general, it is present in various oral formulations like tablets andcapsules in its salt forms, preferably as the fumarate salt. Themolecular formula for its fumarate salt is C₄₂H₅₀N₆O₄S₂·C₄H₄O₄ and ithas a molecular weight of 883.11. The structural formulae of quetiapineand quetiapine fumarate are shown in below Formula I and II,respectively:

Quetiapine fumarate is a white to off-white crystalline powder which ismoderately soluble in water.

Quetiapine was initially approved by the FDA in 1997, it is asecond-generation atypical antipsychotic used in schizophrenia, majordepression, and bipolar disorder. Quetiapine demonstrates a high levelof therapeutic efficacy and low risk of adverse effects during long-termtreatment. Quetiapine is used in the symptomatic treatment ofschizophrenia, in management of acute manic or mixed episodes inpatients with bipolar I disorder, as a monotherapy or combined withother drugs.

Various solid oral dosage forms of quetiapine are known. Quetiapinefumarate is commercially available as an extended release tabletformulation and is marketed under the brand name SEROQUEL XR®.

U.S. Pat. No. 5,948,437 covers the marketed product and discloses asustained release quetiapine tablet formulation wherein the drug iscompressed with a gelling agent to form the tablet.

The commercially available extended release tablet of quetiapinefumarate is used for treatment of schizophrenia, acute treatment ofmanic or mixed episodes associated with bipolar disorder, in treatmentof depressive episodes of bipolar disorders and as an adjunctivetreatment of major depressive disorder.

Solid oral dosage forms are not suitable for patients having difficultyswallowing or with dysphagia as in case of geriatric and pediatricpatients. Further, conventional solid oral dosage forms like tablets andcapsules are intended to be swallowed as whole. The available marketedformulation of quetiapine should not be crushed or chewed, as drugrelease will be compromised. The dosage and administration section ofthe SEROQUEL XR® prescribing information states, “SEROQUEL XR® tabletsshould be swallowed whole and not split, chewed or crushed.” It is alsomandatory as per the SEROQUEL XR® label that the patient should take thetablet without food or with light food. Therefore, there is poorcompliance for the marketed formulation in patients having dysphagia orwith difficulty swallowing.

Dosing regimens for various antipsychotic solid oral dosage formsgenerally include two or three tablets/capsules per day, however, suchregimens were found to be associated with problems such as lack ofconvenience, and more importantly lack of compliance, particularly inpatients with dysphagia and swallowing difficulty. Dysphagia plays acritical role in medication management, since many older adults cannotswallow whole tablets and capsules because of swallowing difficulty.Dysphagia can be caused by difficulties overriding the natural instinctto chew solids/foodstuff before swallowing, or it may be a more complexdisorder of swallowing function affecting the ability to manage all foodand fluid intake. The marketed formulation SEROQUEL XR® (U.S. Pat. No.5,948,437) has not been very helpful in such patients. Further, becausethe control of quetiapine plasma levels is critical during treatment,failures or incidents, such as, the one that can be seen with patientshaving swallowing difficulty, leads to instances of non-compliance ormissed dosing, which can be detrimental to patient health and safety.

Thus, there exists a need for a dosage form or composition of quetiapinewhich provides a better compliance for the patients having dysphagia ordifficulty swallowing or related conditions like where s patient ishesitant or not willing to take medicine.

SUMMARY OF THE INVENTION

The present invention provides an extended release multi-particulatecomposition comprising a plurality of discrete units, each discrete unitcomprising quetiapine or a pharmaceutically acceptable salt thereof andone or more pharmaceutically acceptable excipients, whereby thecomposition can also be sprinkled onto soft foods or edible material orliquids for oral administration.

In another aspect, the present invention provides a stable dosage form,wherein the release profile of the quetiapine or its pharmaceuticallyacceptable salt is not affected by sprinkling the multi-particulatecomposition according to the present invention onto soft foods or ediblematerial or liquids for oral administration. The integrity of thecoating is not influenced by longer exposure to soft foods or ediblematerial or liquids. The dosage form may be taken with or without food.

In some aspects, the multi-particulate composition can be administeredthrough a feeding tube in a long-term care setting to critically illpatients by dispersing in an aqueous media before administration.

In one aspect, the present invention provides discrete units comprisingquetiapine, wherein the discrete units may be in the form of a pellet,granule, spheroid, particle, mini-tablet or bead.

In another aspect, the multi-particulate sprinkle dosage form issubstantially free of food effect and devoid of problems associated withother known marketed formulations such as delay in gastric emptying dueto larger size of tablets or capsules and variability inbioavailability.

In some aspects, the present invention provides an extended releasemulti-particulate sprinkle dosage form comprising a plurality ofdiscrete units, wherein each unit comprises a drug core comprisingquetiapine or a pharmaceutically acceptable salt thereof; at least twocoatings on the drug core wherein one of the at least two coatingscomprises a pH sensitive polymer; and wherein the release of the drug iscontrolled by a combination of the said at least two coatings.

In one aspect, each of the discrete units according to the presentinvention comprises at least two coatings on the drug core to controlthe release of the drug from the core; wherein at least one coatingcomprises a pH sensitive polymer.

In another aspect, each of the discrete units according to the presentinvention comprises at least two coatings on the drug core forcontrolling the release of the drug, wherein one of the at least twocoatings comprises a pH neutral polymer, and the other coating is a pHsensitive polymer.

In yet another aspect, the core of the discrete units comprises anactive ingredient quetiapine or its pharmaceutically acceptable salt,and the coating is devoid of any active ingredient.

In a further aspect according to the present invention, the core isdevoid of a release-controlling polymer.

In one aspect, the extended release multi-particulate sprinkle dosageform according to the present invention comprises a drug core ofquetiapine or a pharmaceutically acceptable salt thereof, coated with apH neutral polymer coating and a pH sensitive polymer coating, whereinthe drug release from the dosage form is controlled by a combined effectof the pH neutral polymer coating and the pH sensitive polymer coating.

DESCRIPTION OF THE INVENTION

As used herein, the word “a” or “plurality” before a noun represents oneor more of the particular noun.

For the terms “for example” and “such as,” and grammatical equivalencesthereof, the phrase “and without limitation” is understood to followunless explicitly stated otherwise. As used herein, the term “about” ismeant to account for variations due to experimental error. Allmeasurements reported herein are understood to be modified by the term“about,” whether or not the term is explicitly used, unless explicitlystated otherwise.

The term “dosage form” as used herein the description, can be usedinterchangeably with the term ‘composition’ or ‘formulation’ or‘pharmaceutical preparation’.

The term “coating” as used herein the description, can be usedinterchangeably with the term “coat” or “layer” around the core.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Methods and materials aredescribed herein for use in the present invention; other, suitablemethods and materials known in the art can also be used. The materials,methods, and examples are illustrative only and not intended to belimiting. All publications, patent applications, patents, and otherreferences mentioned herein are incorporated by reference in theirentirety. In case of conflict, the present specification, includingdefinitions, will control.

The present inventors have developed a stable sprinkle dosage form ofquetiapine in the form of a multi-particulate dosage form comprising aplurality of discrete units. Such dosage form is believed to bebioequivalent to the marketed SEROQUEL XR® formulation and can be easilyadministered by sprinkling on the food. Further, such dosage form whenadministered as a sprinkle over soft food or edible material or liquidfor oral administration, it becomes easier for patients to comply aswell as get the maximum benefit out of therapy.

The present invention relates to an extended release multi-particulatecomposition comprising a plurality of discrete units, each discrete unitcomprising quetiapine or a pharmaceutically acceptable salt thereof andone or more pharmaceutically acceptable excipients, which is sprinkledonto soft foods or edible material or liquids for oral administration.

In another embodiment, the present invention provides a stable dosageform, wherein the release profile of the quetiapine or itspharmaceutically acceptable salt is not affected by sprinkling themulti-particulate composition according to the present invention ontosoft foods or edible material or liquids for oral administration. Theintegrity of the coating is not influenced by longer exposure to softfoods or edible material or liquids. The said dosage form may be takenwith or without food.

In a further embodiment, the multi-particulate composition can beadministered through a feeding tube in a long-term care setting tocritically ill patients by dispersing in an aqueous media beforeadministration.

According to one embodiment of the present invention, the discrete unitsmay be in the form of a pellet, granule, spheroid, particle, mini-tabletor bead.

In another embodiment, the multi-particulate sprinkle dosage formaccording to the present invention is bioequivalent to the marketedquetiapine formulation available under the brand name SEROQUEL XR®.Further, the dosage form is substantially free of food effect and devoidof problems associated with other known marketed formulations such asdelay in gastric emptying due to a larger size of tablets or capsulesand variability in bioavailability.

In one embodiment, the present invention provides an extended releasemulti-particulate sprinkle dosage form comprising a plurality ofdiscrete units, wherein each unit comprises a drug core comprisingquetiapine or a pharmaceutically acceptable salt thereof; at least twocoatings on the drug core wherein one of the at least two coatingscomprises a pH sensitive polymer; and wherein the release of the drug iscontrolled by a combination of said at least two coatings.

In another embodiment, the present invention provides an extendedrelease multi-particulate sprinkle dosage form comprising a plurality ofdiscrete units, wherein each unit comprises a drug core comprisingquetiapine or a pharmaceutically acceptable salt thereof; at least twocoatings on the drug core to control the release of the drug from thecore; wherein at least one coating comprises a pH sensitive polymer.

In yet another embodiment, the extended release multi-particulatesprinkle dosage form according to the present invention comprises aplurality of discrete units, wherein each unit comprises a drug corecomprising quetiapine or a pharmaceutically acceptable salt thereof; atleast two coatings on drug core controlling the release of drug, whereinone of the at least two coatings comprises a pH neutral polymer, and theother coating is a pH sensitive polymer.

In another embodiment, the discrete units according to present inventioncomprise a core and at least two coatings. In another embodiment, thediscrete units comprise a core and more than one coating for modifiedrelease of the drug from the core.

In another embodiment, the core of the discrete units comprises anactive ingredient quetiapine or its pharmaceutically acceptable salt,and the coating is devoid of any active ingredient.

In one aspect of the present invention, the coating may optionallycomprise one or more active ingredients.

In another embodiment of the present invention, the core is devoid of arelease-controlling polymer.

In one embodiment, the multi-particulate sprinkle composition of theinvention may be modulated to provide an extended drug release,controlled drug release, sustained drug release, prolonged drug release,delayed drug release, modified drug release, immediate drug release or acombination of immediate and extended drug release.

The term “granules”, “pellets” or “spheroids” as used herein can be usedinterchangeably, and includes agglomeration from apparent solid powderparticles to large multi-particulates. The agglomeration may be achievedby either granulation, compaction, extrusion, slugging, drug loading orthe like. Such granules, pellets or spheroids have good flow propertyand these may be spherical or oval in shape, and may have a densityhigher than a powder. The granules or pellets or spheroids are coated,in particular, they can be preferably coated with at least onefunctional coating, as described herein. The average diameter of coatedpellets or granules is about 500 μm to about 1800 μm, or about 600 μm toabout 1500 μm. Also included are granules as defined in USP <1151>,which is incorporated herein by reference.

The term “functional coating” in the context of this disclosure refersto one or more controlled release layers, particularly an extendedrelease layer that surrounds a drug core. The term “extended release” asused herein can be used interchangeably with term “controlled release”,“modified release” or “sustained release” and refers to a means ofreleasing an active agent from the dosage form thereof such that it isavailable to the site of absorption by the body over a period of time.

The terms “non-functional coating” or “non-functional film coat” in thecontext of the present disclosure refers to a coating that does notmaterially affect the release of quetiapine or a pharmaceuticallyacceptable salt thereof from the formulation or dosage form. Anon-functional coating or non-functional film coat may still includesome functions not related to the dissolution of quetiapine, such astaste, color, or physical integrity.

The term “sprinkle” as used herein means that the multi-particulatepharmaceutical composition is to be added onto food or any ediblematerial, or liquid, such as water, juices etc., before administration.The pellets or granules or spheroids or particle of themulti-particulate pharmaceutical composition may be packed in sachet orpouch or filled into capsules and may be sprinkled onto soft food oredible material or into a liquid. Alternatively, multi-particulatepharmaceutical composition may also be in the form of a dispersibledosage form which can be dispersed in a liquid to yield a dispersion ofthe individual particles before drinking. The multi-particulatepharmaceutical composition of the present invention is configured so asto be administered by initially opening a sachet or pouch or capsulefilled with it and transferring it to a vehicle, such as a soft food,for example, applesauce, pudding, custard, oatmeal and yoghurt. Then,the vehicle into which the composition is sprinkled is swallowedimmediately. The multi-particulate pharmaceutical composition of thepresent disclosure may be swallowed as a whole when in capsule, and canalso be sprinkled onto the vehicle. Alternatively, geriatric patientswho have difficulty swallowing may add the composition of the presentinvention that has been filled into sachet or pouch or capsule, into aliquid medium, such as water, to obtain a suspension. The suspension maybe then orally administered through, e.g., a nasogastric tube into thestomach.

The term “mixture” as used herein means that the quetiapine or apharmaceutically acceptable salt thereof is mixed uniformly withexcipients of various categories such as stabilizers, alkalizing agents,buffering agents, disintegrants or diluents.

The term “stable” as used herein, refers to a physicochemical stabilitywhich means that the extended/delayed release coat over themulti-particulate composition retain its structural integrity and doesnot rupture in a significant way after exposure to acidic or anyexternal environment for the given time period as determined by the drugrelease and also includes chemically stability which means themulti-particulate composition remains stable when stored:

-   -   under the temperature and humidity conditions of 40° C./75% RH        for at least 6 months; or    -   under the temperature and humidity conditions of 30° C./65% RH        for at least 6 months; or    -   under the temperature and humidity conditions of 25° C./60% RH        for at least 6 months.

The term “pharmaceutically acceptable salt” as used herein means a saltwhich is, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like, commensurate witha reasonable benefit/risk ratio, and effective for their intended use.Representative alkali or alkaline earth metal salts include the sodium,calcium, potassium and magnesium salts, and the like. U.S. Pat. No.4,879,288 (hereafter '288) discloses a process for the preparation ofquetiapine or a pharmaceutically acceptable salt thereof which includeshydrochloride, maleate, fumarate, citrate, phosphonate, methanesulphonate, and hemifumarate salt. The disclosure of '288 also mentionsthat the compound of formula II (quetiapine) can form a salt withphysiologically acceptable organic and inorganic acids likehydrochloride, maleate, fumarate, citrate, phosphonate, methanesulphonate, and hemifumarate salt. Only the hydrochloride, maleate andhemifumarate salts of quetiapine have been prepared, the disclosure ofwhich is incorporated herein by reference.

The term “therapeutically effective amount” as used herein means thatamount of quetiapine or its pharmaceutically acceptable salt that whenadministered to a mammal for treating a disease state, disorder orcondition, is sufficient to effect such treatment. The therapeuticallyeffective amount will vary depending on the compound, the disease andits severity and the age, weight, physical condition and responsivenessof the mammal or human to be treated.

The term “bioequivalent” as used herein has its ordinary meaning asunderstood by those skilled in the art and thus includes, withoutlimitation, a drug or dosage form that, upon administration to asuitable patient population, provides principle pharmacokineticparameters, e.g., AUC and C_(max) that are in the range of 80% to 125%of those provided by a reference standard. Also the terms“bioequivalent” or “bioequivalence”, as used herein are usedinterchangeably and describes pharmaceutical equivalent products thatdisplay comparable bioavailability when studied under similarexperimental conditions. This term also used herein is consistent withthe definitions and concepts assigned to them under the U.S. Drug PriceCompetition and Patent Term Restoration Act of 1984, including theconditions set forth in § 5500)(7)(B), and 21 CFR § 320.24, which areincorporated herein by reference in their entirety. Thus, the term“bioequivalent” as used herein, refers to the equivalent release of thesame drug substance from two or more drug products or formulations whichlead to an equivalent rate and extent of absorption from these productsor formulations. In other words, if a drug product contains a drugsubstance that is chemically identical and is delivered to the site ofaction at the same rate and extent as another drug product, then it isequivalent. Methods to define bioequivalence can be found in 21 CFR320.24, and include (1) pharmacokinetic (PK) studies, (2)pharmacodynamic (PD) studies, (3) comparative clinical trials, and (4)in-vitro studies, which are incorporated herein by reference in theirentireties. Of course, the choice of study used, such as illustratedherein in the present specification, is based upon the site of action ofthe drug and the ability of the study design to compare drug deliveredto that site by the two products.

By the term, “bioavailability”, it refers to the definition and conceptsassigned to this term under the Drug Price Competition and Patent TermRestoration Act of 1984, in particular in § 550(j)(8)(B) and is usedherein consistent with such definition and concept, which isincorporated herein by reference in its entirety.

According to the present invention, particle size of the coatedmulti-particulate discrete units (pellets or granules or spheroids) maybe such that D10 ranges from about 500 μm to about 1100 μm; D50 rangesfrom about 950 μm to about 1250 μm and D90 ranges from about 1150 inn toabout 1800 μm; Preferably D10 ranges from about 700 μm to about 1000 μm;D50 ranges from about 1050 μm to about 1150 μm and D90 ranges from about1200 μm to about 1500 μm.

In one embodiment, the strength of the said quetiapine multi-particulatedosage form is 50 mg, 150 mg, 200 mg, 300 mg, or 400 mg. All dosesstrengths of the composition are expressed as milligrams of quetiapinebase, not as quetiapine fumarate salt.

In another embodiment, the multi-particulate dosage form according tothe present invention may be administered twice or thrice daily (BID orTID) depending upon the dose requirement. In an aspect for instance,when the required dose is 800 mg, two 400 mg sachets may be administeredtogether; when the required dose is 400 mg, a single sachet may beadministered. In another aspect, the dosage form according to presentinvention can be administered as a sprinkle dosage form over soft foodor edible material or liquid for oral administration, thereby a higherdose can be accommodated in a single administration without anyswallowing difficulty. In one embodiment, the multi-particulate dosageform according to the present invention may be administered once daily.

In one embodiment, according to the present invention, the discrete unitof the multi-particulate composition comprises a drug core with one ormore pharmaceutically acceptable excipients, wherein the core is coatedwith at least one functional coating.

In another embodiment according to the present invention, the discreteunit of the multi-particulate composition comprises a drug core andoptionally one or more non-functional coatings.

In an embodiment of the present invention, the core containing theactive ingredient quetiapine or its pharmaceutically acceptable salt iscoated by functional coating layers comprising one extended releasecoating followed by one delayed release coating. In another embodimentof the present invention, the core containing the active ingredientquetiapine or its pharmaceutically acceptable salt is coated byfunctional coating layers comprising a delayed release coating followedby an extended release coating. In another embodiment of the presentinvention, the core containing the active ingredient quetiapine or itspharmaceutically acceptable salt is coated by functional coating layerscomprising an extended release coating, a delayed release coating orcombination thereof. In a related embodiment of the present invention,the core containing the active ingredient quetiapine or itspharmaceutically acceptable salt may also optionally be coated with anon-functional coating.

In a further embodiment, the present invention provides an extendedrelease multi-particulate sprinkle dosage form comprising a plurality ofdiscrete units, wherein each unit comprises: a core comprisingquetiapine or a pharmaceutically acceptable salt thereof, at least onecoating comprising a pH neutral polymer surrounding the core and atleast one coating comprising a pH sensitive polymer surrounding thecore, wherein the drug release from the multi-particulate dosage form iscontrolled by pH sensitive and pH neutral polymers in coatingssurrounding the core.

In yet another embodiment, the present invention provides an extendedrelease multi-particulate sprinkle dosage form comprising a plurality ofdiscrete units, wherein each unit comprises a drug core comprisingquetiapine or a pharmaceutically acceptable salt thereof; an extendedrelease coating and a delayed release coating surrounding the core.

In another embodiment, the present invention provides a controlledrelease sprinkle composition comprising a plurality of particulates,wherein each particulate comprises: a core comprising quetiapine, a pHneutral polymer layer surrounding the core and a pH sensitive polymerlayer surrounding the core, wherein the average particle size (D50) ofcoated particulates is from 0.7 to 1.6 mm or average particle size ofthe coated particulate is less than 1.6 mm.

In an embodiment of the present invention, the multi-particulate dosageform has an extended-release coating which comprises a pH neutralpolymer in an amount of about 5% to about 25% based on the weight ofdrug core.

In one embodiment of the present invention, the multi-particulate dosageform has an extended release coating which comprises a pH neutralpolymer in an amount of about 50% to about 80% based on the weight ofthe extended release coating, preferably about 55% to about 75% based onweight of the extended release coating.

In yet another embodiment of the present invention, the extended releasecoating comprises about 12% to about 32% w/w of the drug core,preferably about 12% to 20% w/w.

In another embodiment of the present invention, the multi-particulatedosage form has a delayed release coating which comprises a pH sensitivepolymer in an amount of about 10% to about 30% based on the weight ofdrug core.

In one embodiment of the present invention, the multi-particulate dosageform has a delayed release coating which comprises a pH sensitivepolymer in an amount of about 55% to about 95% based on the weight ofthe delayed release coating, preferably about 60% to about 90% based onweight of the delayed release coating.

In a further embodiment of the present invention, the delayed releasecoating comprise about 15% to about 45% w/w of the drug core, preferablyabout 15% to about 35% of the drug core.

In one embodiment of the present invention, the active ingredient in thecomposition comprises about 35% to about 70% w/w of a unit dosage form.

In yet another embodiment of the present invention, the activeingredient in the composition comprises about 50% to about 70% w/w ofthe core.

In another embodiment, the present invention provides an extendedrelease multi-particulate sprinkle dosage form comprising a plurality ofdiscrete units, wherein each unit comprises a drug core comprisingquetiapine or a pharmaceutically acceptable salt thereof; an extendedrelease coating and a delayed release coating surrounding the core,wherein the drug release from the multi-particulate dosage form iscontrolled with pH neutral and pH sensitive polymers in the coatingsrespectively. In yet another embodiment, the present invention providesan extended release multi-particulate sprinkle dosage form comprising aplurality of discrete units, wherein each unit comprises a drug corecomprising quetiapine or a pharmaceutically acceptable salt thereof, atleast two coatings on the drug core to control the release of the drugfrom the core, wherein each coating comprises a pH sensitive polymer, apH neutral polymer or a combination thereof.

In one embodiment, the present invention provides an extended releasemulti-particulate sprinkle dosage form comprising a plurality ofdiscrete units, wherein each unit comprises a drug core comprisingquetiapine or a pharmaceutically acceptable salt thereof; an extendedrelease coating comprising a pH neutral polymer and a delayed releasecoating comprising a pH sensitive polymer surrounding the core, whereinthe drug release from the multi-particulate dosage form is controlledwith a combination of pH neutral and/or pH sensitive polymers in thecoatings.

In yet another embodiment, the present invention provides an extendedrelease multi-particulate sprinkle dosage form comprising a plurality ofdiscrete units, wherein each unit comprises a drug core comprisingquetiapine or a pharmaceutically acceptable salt thereof; a delayedrelease coating comprising a pH sensitive polymer and an extendedrelease coating comprising a pH neutral polymer surrounding the core,wherein the drug release from the multi-particulate dosage form iscontrolled with a combination of pH sensitive and/or pH neutral polymersin the coatings.

In a related embodiment, the present invention provides amulti-particulate dosage form wherein the extended-release coating orthe coating with pH neutral polymer comprises a water-insoluble polymer.

In some embodiments, the extended release multi-particulate sprinkledosage form according to present invention comprises a plurality ofdiscrete units, wherein each unit comprises: a drug core comprisingquetiapine or a pharmaceutically acceptable salt thereof; at least twocoatings on drug core for controlling the release of quetiapine from thedrug core wherein one of the at least two coatings comprises a pHsensitive polymer; and wherein said dosage form when administered orallyas a single dose has a mean Cmax under fasting condition in the range ofabout 180 ng/mL to about 450 ng/mL and a mean Cmax under fed conditionin the range of about 250 ng/mL to about 650 ng/mL.

In some embodiments, the extended release multi-particulate sprinkledosage form according to present invention comprises a plurality ofdiscrete units, wherein each unit comprises: a drug core comprisingquetiapine or a pharmaceutically acceptable salt thereof; at least twocoatings on drug core for controlling the release of quetiapine from thedrug core wherein one of the at least two coatings comprises a pHsensitive polymer; and wherein said dosage form when administered orallyas a single dose has a mean AUC_(0-inf) under fasting condition is inthe range of 4000 hr·ng/mL to 4800 hr·ng/mL and a mean AUC_(0-inf) underfed condition in the range of about 4300 hr·ng/mL to 6300 hr·ng/mL.

In one embodiment, the extended release multi-particulate sprinkledosage form according to present invention comprises a plurality ofdiscrete units, wherein each unit comprises: a drug core comprisingquetiapine or a pharmaceutically acceptable salt thereof; at least twocoatings on drug core for controlling the release of quetiapine from thedrug core wherein one of the at least two coatings comprises a pHsensitive polymer; and wherein the said dosage form when administeredorally as a single dose with high fat meals results in not more than(NMT) a 35% change in Cmax or AUC when compared to a similar dosingunder fasting conditions.

In another embodiment, the present invention provides a pharmaceuticalcomposition of quetiapine or a pharmaceutically acceptable salt thereof,wherein said composition is believed to be bioequivalent to an extendedrelease multi-particulate sprinkle dosage form comprising a plurality ofdiscrete units, wherein each unit comprises: a drug core comprisingquetiapine or a pharmaceutically acceptable salt thereof; at least twocoatings on drug core for controlling the release of quetiapine from thedrug core wherein one of the at least two coatings comprises a pHsensitive polymer; and wherein the said dosage form when administeredorally as a single dose with high fat meals results in not more than(NMT) a 35% change in Cmax or AUC when compared to a similar dosingunder fasting conditions.

In a further embodiment, the multi-particulate dosage form according tothe present invention further comprises a pore former in the extendedrelease coating, wherein the ratio of extended release polymer and poreformer in the coating is in a ratio of 70:30 to 99:1 or 75:25 to 97:3 or80:20 to 95:5. Preferably, the ratio is 80:20 to 95:5. In anotherembodiment, the multi-particulate dosage form according to the presentinvention further comprises a pore former in the pH neutral coating,wherein the ratio of pH neutral polymer and pore former in the coatingis in a ratio of 70:30 to 99:1 or 75:25 to 97:3 or 80:20 to 95:5.Preferably the ratio is 80:20 to 95:5.

In an embodiment, the extended release multi-particulate sprinkle dosageform comprises a plurality of discrete units, wherein each unitcomprises: a drug core comprising quetiapine or a pharmaceuticallyacceptable salt thereof; at least two coatings on drug core wherein oneof the at least two coatings comprises a pH sensitive polymer; andwherein the release of the drug is controlled by a combination of saidat least two coatings, wherein the dosage form further comprises a poreformer and the ratio of one of the two coatings and the pore former is80:20 to 95:5.

In one embodiment, the multi-particulate sprinkle dosage form accordingto the present invention comprises coated particulates having a particlesize in range of 0.5 mm-1.6 mm, and said sprinkle dosage form releasesnot more than 20% of quetiapine after two hours, when measured in aUnited States Pharmacopeia (USP) type I dissolution apparatus, 200 rpm,at a temperature of 37° C.±0.5° C. in 900 mL of pH 4.80 citrate buffermedia.

In a further embodiment, the present invention provides a pharmaceuticalcomposition of quetiapine or a pharmaceutically acceptable salt thereof,wherein said composition is believed to be bioequivalent to an extendedrelease multi-particulate sprinkle dosage form comprising a plurality ofdiscrete units, wherein said multi-particulate sprinkle dosage formcomprises coated particulates having a particle size in range of 0.5mm-1.6 mm, and said sprinkle dosage form releases not more than 20% ofquetiapine after two hours when measured in a United States Pharmacopeia(USP) type I dissolution apparatus, 200 rpm, at a temperature of 37°C.±0.5° C. in 900 mL of pH 4.80 citrate buffer media.

In another embodiment of the present invention, the multi-particulatedosage form releases about 30% to about 70% of quetiapine at eighthours, when measured in a United States Pharmacopeia (USP) type Idissolution apparatus, 200 rpm, at a temperature of 37° C.±0.5° C. in1000 mL of pH 6.60 citrate buffer follow on media after 5th hour of pH4.80 citrate buffer media.

In one embodiment of the present invention, the multi-particulate dosageform releases not more than 10% of quetiapine after 2 hours, whenmeasured in a United States Pharmacopeia (USP) type I dissolutionapparatus, 200 rpm, at a temperature of 37° C.±0.5° C. in 1000 mL of pH0.1 N HCl (40 mesh basket).

In another embodiment of the present invention, the multi-particulatedosage form releases not more than 30% of quetiapine when measured in aUnited States Pharmacopeia (USP) type I dissolution apparatus, 200 rpm,at a temperature of 37° C.±0.5° C. in 1000 mL of pH 6.60 phosphatebuffer follow on media (after 2 hours dissolution in 0.1 NHCl) after1^(st) hour of buffer stage (40 mesh basket).

In another embodiment of the present invention, the multi-particulatedosage form releases about 40% to about 70% of quetiapine when measuredin a United States Pharmacopeia (USP) type I dissolution apparatus, 200rpm, at a temperature of 37° C.±0.5° C. in 1000 mL of pH 6.60 phosphatebuffer follow on media (after 2 hours dissolution in 0.1 NHCl) after6^(th) hour of buffer stage (40 mesh basket).

In another embodiment of the present invention, the multi-particulatedosage form releases about 40% to about 70% of quetiapine when measuredin a United States Pharmacopeia (USP) type I dissolution apparatus, 200rpm, at a temperature of 37° C.±0.5° C. in 1000 mL of pH 6.60 phosphatebuffer follow on media (after 2 hours dissolution in 0.1 NHCl) after22^(nd) hour of buffer stage (40 mesh basket).

In one embodiment, the present invention provides a dosage form which isbelieved to be bio-equivalent to an extended release multi-particulatesprinkle dosage form comprising a plurality of discrete units, whereineach unit comprises: a drug core comprising quetiapine or apharmaceutically acceptable salt thereof; an extended release coatingand a delayed release coating surrounding the core, wherein the drugrelease from the multi-particulate dosage form is controlled by pHsensitive and pH neutral polymers in the coatings, wherein the AUC andCmax is in the range 80-125%.

In another embodiment, the extended release multi-particulate sprinkledosage form according to the present invention comprises a plurality ofdiscrete units, wherein each unit comprises: a drug core comprisingquetiapine or a pharmaceutically acceptable salt thereof; at least twocoatings on drug core wherein one of the at least two coatings comprisesa pH sensitive polymer; and wherein the release of the drug iscontrolled by a combination of the said at least two coatings, whereinadministration of the sprinkle dosage form under fasting conditionsprovides AUC and Cmax values within the acceptable range of 80-125%.

In yet another embodiment, there is provided a pharmaceuticalcomposition of quetiapine or a pharmaceutically acceptable salt thereof,wherein said composition is believed to be bioequivalent to an extendedrelease multi-particulate sprinkle dosage form comprising a plurality ofdiscrete units, wherein each unit comprises: a drug core comprisingquetiapine or a pharmaceutically acceptable salt thereof; at least twocoatings on the drug core wherein one of the at least two coatingscomprises a pH sensitive polymer; and wherein the release of the drug iscontrolled by a combination of said at least two coatings, whereinadministration of the sprinkle dosage form under fasting conditionsprovides AUC and Cmax values within the acceptable range of 80-125%.

In a further embodiment, the present invention provides an extendedrelease multi-particulate sprinkle dosage form comprising a plurality ofdiscrete units, wherein each unit comprises: a drug core comprisingquetiapine or a pharmaceutically acceptable salt thereof; an extendedrelease coating and a delayed release coating surrounding the core,wherein the drug release from the multi-particulate dosage form iscontrolled by pH sensitive and pH neutral polymers in the coatings, andthe core is devoid of any release controlling polymer.

In one embodiment of the present invention, the multi-particulatecomposition is substantially free of an immediate release component.

In an embodiment of the present invention, the extended release coatingcomprises a combination of a pH neutral and a pH sensitive polymer.

The term “pH neutral polymer(s)” as used herein includes, but is notlimited to, cellulose ethers such as ethyl cellulose; cellulose esters,polymethacrylic acid esters copolymers, e.g., Eudragit® NE 30 D, andEudragit® NE 40 D aminoalkyl methacrylate copolymers, e.g., Eudragit® RL100, Eudragit® RL PO, Eudragit® RS PO, and Eudragit® RS 100; polyvinylacetate, copolymers of polyvinyl acetate and polyvinyl pyrrolidone, or amixture thereof. Preferably, the pH neutral polymer is ethyl cellulose.

The term “pH sensitive polymer(s)” as used herein includes, but is notlimited to, acrylic acid derivatives, e.g., methyl acrylate acrylic acidcopolymer, methyl acrylate methacrylic acid copolymer, butyl acrylatestyrene acrylic acid copolymer, methacrylic acid methyl methacrylatecopolymer (e.g., Trade-names: Eudragit L 100 and Eudragit S, availablefrom Rohm Pharma), methacrylic acid ethyl acrylate copolymer, e.g.,Eudragit L 100-55, available from Rohm Pharma, methyl acrylatemethacrylic acid octyl acrylate copolymer; cellulose derivatives e.g.cellulose acetate phthalate, cellulose acetate succinate, celluloseacetate maleate, cellulose acetate trimelliate, cellulose benzoatephthalate, cellulose propionate phthalate, methylcellulose phthalate,carboxymethylethylcellulose, ethylhydroxyethylcellulose phthalate,polyvinyl derivatives, e.g., polyvinyl alcohol phthalate,polyvinylacetal phthalate, polyvinyl butylate phthalate,polyvinylacetoacetal phthalate and maleic acid copolymers, or a mixturethereof.

In one embodiment, the present invention provides a high drug loadsprinkle dosage form for nasogastric administration, wherein said dosageform comprises: quetiapine or its pharmaceutically acceptable salt in adose range of 200-400 mg twice or thrice daily; which can beadministered to psychiatric patients, or patients who are unconscious orare having swallowing difficulty. In a related embodiment of thisaspect, the multi-particulate composition is sprinkled onto soft foodsor edible material or liquids.

In yet another embodiment of the present invention, themulti-particulate composition is sprinkled onto soft foods, for example,applesauce, yogurt, cottage cheese, peaches purees, pears purees, lycheepurees, apricots purees, grapes purees, strawberries purees, raspberriespurees, or bananas purees at the time of administration. In a furtherembodiment of the present invention, the multi-particulate compositionis sprinkled onto liquids, for example, cranberry juice, grape fruitjuice, orange juice, pineapple juice, mango juice, apple juice,vegetable juice, tomatoes juice, water or milk at the time ofadministration. In a related embodiment of this invention, themulti-particulate composition when sprinkled onto soft foods or ediblematerial or liquids are stable for at least about 15 minutes withoutaffecting the stability of the extended release coating.

In another embodiment, the composition according to present invention isa multi-particulate dosage comprising a plurality of discrete units,where in each unit is separately coated thereby in case of accidentalrupture of two or three pellets or granules there won't be anysignificant dose dumping.

In a further embodiment, the multi-particulate composition according topresent invention also reduces the variability in bioavailability as thegastric emptying of the pellets or granules are not significantlyimpacted due to the size of pellets less than 2 mm.

In yet another embodiment of the present invention, themulti-particulate composition when sprinkled onto soft foods or ediblematerial or liquids is stable to be administered immediately with food.In another embodiment of this aspect, the multi-particulate compositionis suitable for administration to a patient via a feeding tube. In afurther embodiment of this aspect, the feeding tube is a nasogastric(NG) tube or a gastric (G) tube.

In one embodiment of the present invention, the multi-particulatecomposition when dispersed in an aqueous media is stable whenadministered through a feeding tube after holding for at least 10minutes.

In another embodiment, the present invention provides an extendedrelease multi-particulate sprinkle dosage form comprising a plurality ofdiscrete units, wherein the said multi-particulate sprinkle dosage formcomprise coated discrete units having a particle size in range of 0.5mm-1.6 mm, wherein the discrete units when exposed to water for 60minutes in a syringe, and then passed through a 12 French nasogastrictube into a dissolution medium of 0.1N HCl, releases not more than 0.5%of quetiapine N-oxide impurity or not more than 0.5% of impurity C after2 hours, when placed in 1000 mL of 0.1N HCl at 100 rpm in USP apparatusI.

In one embodiment, the extended release multi-particulate sprinkledosage form according to present invention is stable for at least 6months under storage conditions of 40° C./75% RH. In one embodimentaccording to present invention, the multi-particulate sprinkle dosagehas controlled level of impurities after storage period of at least 6months, wherein the dosage form contains not more than 0.5% ofquetiapine N-oxide impurity (USP related compound H), contains not morethan 0.5% of impurity C (USP related compound G), any unspecifieddegradation product not more than 0.5% and total impurities not morethan 1% by weight of quetiapine.

In some embodiments, the extended release multi-particulate sprinkledosage form according to present invention is stable for at least 6months under storage conditions of 40° C./75% RH. In one embodimentaccording to present invention, the multi-particulate sprinkle dosagehas controlled level of impurities after a storage period of at least 6months, wherein the dosage form contains not more than 0.2% ofquetiapine N-oxide impurity (USP related compound H), contains not morethan 0.2% of impurity C (USP related compound G), any unspecifieddegradation product not more than 0.2% and total impurities not morethan 0.6% by weight of quetiapine.

In another embodiment, the present invention provides an extendedrelease multi-particulate sprinkle dosage form comprising a plurality ofdiscrete units, wherein the said multi-particulate sprinkle dosage formcomprise coated discrete units having a particle size in range of 0.5mm-1.6 mm, wherein the discrete units when exposed to water for 60minutes in a syringe, and then passed through a 12 French nasogastrictube into a dissolution medium of 0.1N HCl, releases not more than 0.2%of quetiapine N-oxide impurity or not more than 0.2% of impurity C after2 hours, when placed in 1000 mL of 0.1N HCl at 100 rpm in USP apparatusI.

In another embodiment according to present invention, themulti-particulate sprinkle dosage form is stable for at least 6 monthsunder storage condition of 40° C./75% RH, wherein the water content ofthe dosage form is not more than 8.0%, preferably not more than 5.0,more preferably not more than 3.5%, by weight of the composition.

In a preferred embodiment of the present invention, themulti-particulate composition comprising coated discrete units may befilled into a pouch or a sachet.

In yet another embodiment of the present invention, the weight ofpellets or granules or spheroids filled in a sachet or a pouch may rangefrom about 100 mg to about 200 mg for 50 mg strength of quetiapine;about 300 mg to about 600 mg for 150 mg; about 400 mg to about 800 mgfor 200 mg strength of quetiapine; about 600 mg to about 1200 mg for 300mg strength and about 800 mg to about 1600 mg for 400 mg strength ofquetiapine.

The multi-particulate composition of present invention may furthercomprise pharmaceutically acceptable excipients, for example, binders,diluents, disintegrants, pore-formers, lubricants/glidants, surfactants,sweeteners, anti-tacking agents, opacifiers, anti-foaming agents,coloring agents, taste masking/flavoring agents, or a mixture thereof.

Examples of diluents that may be used in the present compositioninclude, but are not limited to, microcrystalline cellulose, lactose,sorbitol, calcium dihydrogen phosphate dihydrate, calciumphosphate-dibasic, calcium phosphate-tribasic, calcium sulfate,silicified microcrystalline cellulose, mannitol, disaccharide sugars,starch, pregelatinized starch, or a mixture thereof.

Examples of binders that may be used in the present composition include,but are not limited to, corn starch, pregelatinized starch,microcrystalline cellulose, silicified microcrystalline cellulose,methyl cellulose, hydroxypropyl cellulose (HPC-L), methylcellulose,carboxymethyl cellulose sodium, guar gum, polyvinylpyrrolidone, or amixture thereof.

Examples of plasticizers that may be used in the present compositioninclude, but are not limited to, tributyl citrate, dibutyl sebacate,acetyl tributyl citrate, glyceryl monostearate, diethyl phthalate,castor oil, acetylated monoglycerides, diacetylated monoglycerides,cetyl alcohol, or a mixture thereof. The addition of plasticizer in thepresent invention helps in maintaining integrity of coating layer(s)while achieving a desired rate of release of quetiapine frommulti-particulates.

Examples of lubricants and glidants that may be used in the presentcomposition include, but are not limited to, colloidal anhydrous silica,stearic acid, magnesium stearate, glyceryl behenate, calcium stearate,sodium stearyl fumarate, stearic acid, talc, microcrystalline wax,yellow beeswax, white beeswax, or a mixture thereof.

Examples of the disintegrants that may be used in the presentcomposition include, but are not limited to, crospovidone, sodium starchglycolate, sodium croscarmellose, guar gum, carboxymethylcellulose, lowviscosity hydroxypropylcellulose, potassium polacrilin, or a mixturethereof.

Examples of surfactants that may be used in the present compositioninclude, but are not limited to, sorbitan monostearate, polyoxythylenesorbitan monostearate, e.g., Polysorbate 60 or Polysorbate 80,non-ethoxylated glyceryl monostearate, cetomacrogol, cetostearylalcohol, sodium stearoyl lactylate, lecithin, or a mixture thereof.

Examples of sweeteners that may be used in the present compositioninclude, but are not limited to, sucrose, sucralose, sorbitol, xylitol,dextrose, fructose, maltose, maltitol, acesulfame potassium, aspartame,saccharin, saccharin sodium, glucose, cyclamate, sodium cyclamate, or amixture thereof.

Examples of opacifiers that may be used in the present compositioninclude, but are not limited to, titanium dioxide, silicon dioxide,talc, calcium carbonate, behenic acid, or a mixture thereof.

Examples of anti-tacking agents that may be used in the presentcomposition include, but are not limited to, talc, colloidal silicondioxide, or a mixture thereof.

Examples of anti-foaming agents that may be used in the presentcomposition include, but are not limited to, silicon based surfactantslike polydimethylsiloxanes, e.g., simethicone; vegetable oils; waxes;hydrophobic silica; polyethylene glycol, or a mixture thereof.

Suitable solvents are selected from water, methyl alcohol, ethylalcohol, isopropyl alcohol, n-butyl alcohol, acetone, acetonitrile,chloroform, methylene chloride, water, or a mixture thereof.

The coloring agents and flavoring agents of the present invention may beselected from any FDA approved suitable colors or flavors for oral use.

Coating may be carried out by using any conventional coating techniquesknown in the art, such as, spray coating in a conventional coating pan,fluidized bed processor, or dry powder coating, or a combinationthereof.

The extended release multi-particulate composition of the presentinvention can be prepared by various methods including fluidized bedgranulation, wet granulation, solvent evaporation, spray drying, or acombination thereof.

In yet another embodiment, the present invention provides a method forpreparing a multi-particulate composition of quetiapine.

In one embodiment, the present invention provides use of a combinationof at least two coatings for preparation of an extended releasemulti-particulate sprinkle dosage form of quetiapine, wherein out of theat least two coatings on a drug core at least one coating comprises a pHsensitive polymer; and wherein the release of the drug is controlled bya combination of the at least two coatings.

In another embodiment, the present invention provides an extendedrelease multi-particulate sprinkle dosage form prepared by a processcomprising mixing quetiapine or its pharmaceutically acceptable saltwith suitable excipients and at least two coatings on a drug corewherein one of the at least two coatings comprises a pH sensitivepolymer; and wherein the release of the drug is controlled by acombination of the at least two coatings.

In a further embodiment, the present invention provides a process ofpreparation of an extended-release multi-particulate compositioncomprising a plurality of discrete units comprising quetiapine or apharmaceutical acceptable salt thereof, wherein the process comprises:

-   -   i. mixing quetiapine or a pharmaceutical acceptable salt thereof        with suitable pharmaceutical acceptable excipients in a dry mix        followed by granulation using a suitable technique;    -   ii. extruding the resultant from step i) followed by        spheronization;    -   iii. drying the resulting drug containing spheroids or granules        or pellets from step ii);    -   iv. drying and sifting the resultant from step iii);    -   v. coating the drug containing core with a suitable pH neutral        polymer;    -   vi. coating the core further with a suitable pH sensitive        polymer; and    -   vii. lubricating the coated core followed by filling into a        suitable sachet or pouch or capsule.

In a further embodiment, the present invention provides a process ofpreparation of an extended-release multi-particulate compositioncomprising a plurality of discrete units comprising quetiapine or apharmaceutical acceptable salt thereof, wherein the process comprises:

-   -   i. mixing quetiapine or a pharmaceutical acceptable salt thereof        with suitable pharmaceutical acceptable excipients in a dry mix        followed by granulation using a suitable technique;    -   ii. extruding the resultant from step i) followed by        spheronization;    -   iii. drying the resulting drug containing spheroids or granules        or pellets from step ii);    -   iv. drying and sifting the resultant from step iii);    -   v. coating the drug containing core with a suitable pH sensitive        polymer;    -   vi. coating the core further with a suitable pH neutral polymer;        and    -   vii. lubricating the coated core followed by filling into a        suitable sachet or pouch or capsule.

In yet another related embodiment, the composition according to thepresent invention may further comprise a suitable non-functionalcoating.

In one embodiment, the present invention provides a method of treatingvarious psychotic disorders. In an aspect, the present inventionprovides a method of treating schizophrenia. In another aspect, there isprovided a method of treatment of maniac or mixed episodes associatedwith bipolar disorders. In a related aspect, the present invention alsoprovides a monotherapy or an adjunct therapy with other known therapiesfor the treatment of manic or bipolar disorders. In a further aspect,the present invention provides an adjunctive treatment of a majordepressive disorder.

In a further embodiment, the present invention provides a method oftreating schizophrenia, major depression or bipolar disorder, saidmethod comprising orally administering to a human in need thereof, themulti-particulate pharmaceutical composition of quetiapine according tothe present invention.

In one embodiment, the present invention provides a use of an extendedrelease multi-particulate composition comprising a plurality of discreteunits of quetiapine or its pharmaceutically acceptable salt according tothe present invention for treatment of schizophrenia, in management ofacute manic or mixed episodes in patients with bipolar disorder, as amonotherapy or in combination with other drugs.

In one embodiment, the stable multi-particulate pharmaceuticalcomposition according to the present invention is filled into a sachetor pouch or capsule with a controlled opening to avoid spillage of thecontents of such packing. This is particularly helpful for geriatricpatients or patients with poor locomotors control who have difficultyopening the sachet or pouch or capsule to empty the contents onto softfood or edible material or liquid. Particularly, the absence of finepowders in the multi-particulate pharmaceutical composition can avoidloss of the composition which may result from blowing of the fine powderwhile being emptied from the capsule or pouch onto the carrier solid orliquid food contents. Alternatively, the granules, pellets or spheroidscan be administered from a device which dispenses them directly onto thesoft food or edible material or liquid.

The following non-limiting examples illustrate the scope of the presentdisclosure without any limitation thereto. It is to be understood thatthe disclosed embodiments are merely exemplary of the invention, whichcan be embodied in various forms.

EXAMPLES Example 1

Various batches of quetiapine compositions were prepared with differentexcipients to evaluate the impact of pH sensitive and pH neutralpolymer:

Ingredients Example 1A Example 1B Quetiapine Fumarate 230.270 230.270Tri sodium citrate anhydrous 65.800 65.800 Avicel PH101 41.930 41.930Pregelatinized starch 20.000 20.000 (Lycatab PGS) Colloidal anhydroussilica 2.000 2.000 (Aerosil 200) Core pellets 360.00 360.00 Opadry18.000 18.000 Sub coated pellets wt. 378.00 378.00 Ethyl cellulose 20cps 6.910 6.910 HPMC E5 8.446 8.446 Dibutyl sebacate 3.543 3.543 ERcoated pellets 396.900 396.900 DR/ER coating DR ER Eudragit L 100 55(Enteric) 12.600 — Ethyl cellulose — 8.060 HPMC E5 3.150 8.060 Dibutylsebacate 2.580 3.720 Talc 1.550 — DR /ER coated pellets wt. 416.78416.74 Talc 1.220 1.260 Total pellet weight 418.00 418.00

TABLE 1 Bio results of Example 1A and 1B: Fasting study results Example1A Example 1B Based on comparison ln Cmax ln AUC_(0-t) ln AUC_(0-inf) lnCmax ln AUC_(0-t) ln AUC_(0-inf) of Test/Reference (ng/ml) (ng · hr/mL)(ng · hr/mL) (ng/mL) (ng · hr/mL) (ng · hr/mL) Based on Ratio (%) 118.6391.84 94.45 160.13 77.79 85.90 comparison (T/R) of T/R 90% 96.84- 79.12-81.36- 130.03- 66.75- 73.48- Confidence 145.31 106.60 109.65 197.2090.65 100.42 Interval

Observation: From the Table 1 fasting study, it was found that thesamples from Example 1B showed risk of supra bioavailability withrespect to Cmax as it did not have a pH sensitive polymer. Cmax was onthe higher side 160% (target 100% in ratio Test/Reference) when a pHneutral polymer alone was used. When a combination of a pH sensitive anda pH neutral polymer was used in the multi-particulate system, the Cmaxwas within the acceptable range of 80-125%.

Example 2

Mixture of two different types of pellets: Pellet 1—70% w/w and Pellet2—30% w/w, were filled in a single sachet or pouch.

Composition of Pellet 1 (70% w/w)

Ingredients Quantity Drug Core Pellets mg/unit dose Quetiapine Fumarateeq. to quetiapine 200 mg 230.270 Microcrystalline cellulose (AvicelPH101) 75.730 Tri-Sodium Citrate dihydrate 50.000 Pregelatinized starch(Lycatab PGS) (Part A) 7.000 Pregelatinized starch (Lycatab PGS) (PartB) 15.000 Colloidal anhydrous silica 2.000 Purified water q.s. Corepellet weight 380 DR Coating Eudragit L30D 55 (solids polymer) 8.444 PEG400 1.267 Talc 1.689 Purified water q.s. DR coated weight 391.4 ERCoating EC solids polymer (Aquacoat ARC I of II) 63.865 Guar gum(Aquacoat ARC II of II) 9.124 Dibutyl sebacate 15.966 Talc 8.895Purified water q.s. ER coated pellet wt. 489.25 Top Coat Sodium AlginateCR8133 39.453 PEG 6000 5.793 Talc 52.604 Purified water q.s. Totalpellet weight per unit 587.1Composition of Pellet 2 (30% w/w)

Ingredients Quantity Drug Core Pellets mg/unit dose Quetiapine Fumarateeq. to quetiapine 200 mg 230.270 Microcrystalline cellulose (AvicelPH101) 75.730 Tri-Sodium Citrate dihydrate 50.000 Pregelatinized starch(Lycatab PGS) (Part A) 7.000 Pregelatinized starch (Lycatab PGS) (PartB) 15.000 Colloidal anhydrous silica 2.000 Purified water q.s. Corepellet weight 380 DR Coat Hypromellose Acetate Succinate HF 95.00 Talc19.00 Isopropyl alcohol q.s. Purified water q.s. DR coated pellet wt.494.00 Top Coat Sodium Alginate CR8133 39.84 PEG 6000 5.85 Talc 53.12Total weight 592.80

TABLE 2 Bio results of Example 2 in fasting and food effect conditions:ln Cmax ln AUC_(0-t) ln AUC_(0-inf) (ng/mL) (ng · h/mL) (ng · h/mL)Quetiapine: Fasting Equivalence Ratio of Test & 124.83  87.95  86.81Reference (90% CI) Quetiapine: Food Effect Ratio of Test & 110.79 108.05107.97 Reference (90% CI)

Observation: From the Table 2 Bio-study it was found that the presenceof food showed little or no food effect.

Example 3

200 mg equivalent of quetiapine formulation were prepared as per thecomposition shown below:

% w/w per Sachet S. No Ingredients A B C D E F G H Drug core 1Quetiapine 230.270 230.265 230.265 230.265 230.265 230.265 230.265230.265 fumarate 2 Microcrystalline 75.730 75.735 75.735 75.735 75.73575.735 75.735 75.735 cellulose (PH101) 3 Tri Sodium 50.000 50.000 50.00050.000 50.000 50.000 50.000 30.000 Citrate dihydrate 4 Pregelatinized22.000 22.000 22.000 22.000 22.000 22.000 22.000 22.000 starch 6Colloidal 2.000 2.000 2.000 2.000 2.000 2.000 2.000 2.000 anhydroussilica 7 Purified water q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. ERCoating 8 Ethyl cellulose 62.005 39.683 43.084 39.683 49.603 62.00449.603 39.683 dispersion (Solid) 9 Guar gum 8.858 5.669 2.241 5.6697.086 8.858 7.086 5.669 10 Dibutyl sebacate 15.501 9.921 9.921 9.92112.401 15.501 12.401 9.921 11 Talc 8.636 5.527 5.527 5.527 6.910 8.6376.910 5.527 12 Purified water q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. DRcoating 13 Eudragit L30D 55 70.370 65.304 65.304 70.528 54.044 39.97067.556 65.304 (solid) 14 Talc 14.074 13.061 13.061 8.816 8.107 5.99610.133 13.061 15 PEG 400 10.556 9.795 9.795 8.816 10.809 7.994 13.5119.795 16 Purified water q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. Top Coat17 HPMC 6 CPS 19.136 — — — — — — — 18 Carbopol 971 P 1.222 — — — — — — —19 Talc 8.144 — — — — — — — 20 Isopropyl alcohol q.s. — — — — — — — 21Purified water q.s. — — — — — — — Lubrication 22 Talc — 5.290 5.2905.290 5.290 5.290 5.290 5.290 Final Weight 598.502 534.250 534.250534.250 534.250 534.250 552.672 514.250

Manufacturing Process Example 3A

-   -   1. Quetiapine, microcrystalline cellulose, part of pregelatinsed        starch and colloidal silicon dioxide were mixed in a dry mix        followed by the addition of sodium citrate and remaining part of        pregelatinised starch in purified water;    -   2. The resulting mixture from step 1) was then granulated in a        rapid mixture granulator;    -   3. The resulting mass from step 2) was extruded and spheronized        to form particulates as spheroids/pellets/granules which were        subjected to drying and sifting;    -   4. A dispersion of ethyl cellulose was prepared, guar gum and        dibutyl sebacate and purified water added to it;    -   5. Then the step 3) sifted particulates were coated with the        dispersion of step 4) to obtain extended release coated cores.    -   6. A delayed release coat of Eudragit L 30 D 55, polyethylene        glycol, talc and purified water was coated onto the step 5)        extended release coated cores.    -   7. HPMC and Carbopol were dissolved in isopropyl alcohol and        water followed by coating the delayed release coated particles        of step 6) followed by lubrication with talc and filling into        sachet.

Manufacturing Process Example 3(B-H)

-   -   1. Quetiapine, microcrystalline cellulose, part of pregelatinsed        starch and colloidal silicon dioxide were mixed in dry mix        followed by addition of sodium citrate and remaining part of        pregelatinised starch in purified water;    -   2. The resulting mixture from step 1) was then granulated in a        rapid mixture granulator;    -   3. The resulting mass from step 2) was extruded and spheronized        to form spheroids/pellets which were subjected to drying and        sifting;    -   4. A dispersion of ethyl cellulose was prepared, guar gum and        dibutyl sebacate and purified water added to it;    -   5. Then the step 3) sifted spheroids/pellets were coated with        the dispersion of step 4) to obtain extended release coated        cores.    -   6. A delayed release coat of Eudragit L 30 D 55, polyethylene        glycol, talc and purified water was coated onto the step 5)        extended release coated cores.    -   7. The resulting delayed release coated core particles were then        lubricated with talc and filled into sachet.

TABLE 3 Bio results of Example 3B in fasting and food effect studyconditions: ln Cmax ln AUC_(0-t) ln AUC_(0-inf) Ratio of Test andReference (ng/mL) (ng · hr/mL) (ng · hr/mL) Fasting Condition Ratio (%)(T/R) 106.89  94.79  95.23 90% Confidence Interval 91.50-124.86 87.92-102.19  88.48-102.49 Intra-Subject CV (%)  27.07  12.92  12.63Food Effect Study Ratio (%) (T/R) 111.48 112.17 110.95 90% ConfidenceInterval 96.95-128.20 103.85-121.15 102.89 -119.65 Intra-Subject CV (%) 24.25  13.24  12.96

Observation: From Table 3, fasting data and the food effect data showsthat food has no effect on the drug release from the multi-particulatecomposition according to the present invention and the Cmax was withinthe acceptable range of 80-125%.

Example 4

50 mg, 200 mg and 400 mg equivalent of quetiapine formulations wereprepared as per the compositions shown below:

% w/w per Sachet S. No 50 mg Strength 200 mg Strength 400 mg StrengthIngredients A B C D E F G H I Drug core Quetiapine 57.571 57.556 57.566230.270 230.265 230.265 460.539 460.530 460.389 fumarate equivalent toQuetiapine base Microcrystalline 17.491 19.592 18.934 78.132 75.73581.242 148.91 151.47 153.35 cellulose Sodium Citrate 13.5 11.8 12.50048.0 50.0 53.0 91.500 100 104 (tri sodium citrate dihydrate)Pregelatinized 6.3 4.8 5.500 24 22 18 48 44 39 starch Colloidal 1 0.70.5 5 2 4 8 4 6 Silicon dioxide Purified water* q.s. q.s. q.s. q.s. q.s.q.s. q.s. q.s. q.s. Weight of Core 95.847 94.448 95.0 385.402 380.0386.507 756.949 760.0 762.739 ER Coating Ethyl cellulose 10.227 10.8369.921 38.643 39.683 41.503 85.554 79.366 74.756 aq. dispersion(Solid)^(#) Guar gum 1.65 1.81 1.417 5.137 5.669 4.328 12.160 11.33815.312 Dibutyl 2.92 3.17 2.48 8.789 9.921 7.786 17.435 19.842 16.811sebacate Talc 1.41 1.16 1.382 5.231 5.527 3.245 9.853 11.054 12.348Purified water* q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. Weight of112.054 111.424 110.2 443.202 440.8 443.369 881.951 881.6 881.966extended release pellets DR coating Methacrylic 17.505 15.807 16.32664.461 65.304 62.952 134.463 130.608 135.392 acid copolymer DispersionUSNF equivalent to dry polymer{circumflex over ( )} Polyethylene 3.1412.865 2.449 8.819 9.795 11.138 18.651 19.590 21.262 glycol 400 Talc 3.862.953 3.265 14.561 13.061 12.465 23.412 26.122 19.819 Purified water*q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. Weight of 136.56 133.049145.676 531.043 528.96 529.924 1058.477 1057.92 1058.433 delayed releasepellets Lubrication Talc 1.1 0.81 0.960 5.421 3.840 4.876 8.551 7.68011.132 Weight of 137.66 133.859 133.200 536.464 532.800 534.8 1067.0281065.600 1069.565 lubricated pellets *Evaporates during processing;^(#)30% of dispersion taken in solid form; {circumflex over ( )}30% ofdispersion taken as dry polymer; aq. Aqueous

Stability Data: The samples of Example 4 were kept for stability studiesfor 1, 3 and 6 months, respectively. The stability analysis was doneusing an assay method for determining the content of drug in the storedstability samples of Example 4. The stability analysis was also done byperforming dissolution studies at 0.1N HCl medial 1000 ml for 2 hour,followed by pH 6.60 phosphate buffer media (1000 ml); in USP-I with (40mesh basket) at 200 RPM. The details of stability study results areprovided in below Table 4 and Table 5:

TABLE 4 Stability study data of 50 mg and 200 mg strength samples:Strength 50 mg 200 mg Stage-> 40° C./75% RH 40° C./75% RH Test Spec.Initial 1M 3M 6M Initial 1M 3M 6M Assay 90-110% 98.6 98.8 104.8 104.698.7 102.3 101.1 99.4 Dissolution Acid stage - 2 hr NMT 10% 0 1 0 0 0 01 0 Buffer Stage - 1 hr NMT 30% 19 20 16 18 18 18 21 19 Buffer stage - 6hr 40%-70% 59 56 55 50 53 54 58 54 Buffer Stage - 22 hr NLT 80% 99 96 9495 93 97 101 92 Related Substance Quetiapine N Oxide NMT 0.2% 0.03 0.040.05 0.06 0.03 0.04 0.05 0.05 (USP Related compound H) Impurity C NMT0.2% BLQ BLQ 0.01 0.01 BLQ BLQ 0.01 0.01 (USP Related compound G) Anyindividual NMT 0.2% 0.01 0.04 0.01 0.01 BLQ 0.04 0.01 0.01 unspecifieddegradation product Total impurities NMT 0.6% 0.03 0.04 0.10 0.1 0.030.04 0.09 0.11 Water by KF NMT 8.0% 1.87 2.01 2.07 2.29 1.75 1.95 1.842.21 Note: BLQ—below limit of quantification; NMT—Not More Than; NLT—NotLess Than; USP—United States Pharmacopoeia; HCl—Hydrochloric Acid;

TABLE 5 Stability study data of 400 mg strength samples: Strength 400 mgStage-> 40° C./75% RH Test Spec. Initial 1M 3M 6M Assay 90-110% 101.198.9 98.6 98.1 Dissolution: Acid stage - 2 hr NMT 10% 0 0 0 0 BufferStage - 1 hr NMT 30% 18 15 11 21 Buffer stage - 6 hr 40%-70% 51 48 47 51Buffer Stage - 22 hr NLT 80% 88 89 92 94 Related Substance: Quetiapine NOxide NMT 0.2% 0.03 0.04 0.05 0.06 (USP Related compound H) Impurity CNMT 0.2% BLQ BLQ 0.01 0.004 (USP Related compound G) Any individual NMT0.2% BLQ 0.04 0.01 0.02 unspecified degradation product Total impuritiesNMT 0.6% 0.03 0.08 0.12 0.14 Water by KF NMT 8.0% 1.85 1.79 1.74 2.99Note: BLQ—below limit of quantification; NMT—Not More Than; NLT—Not LessThan; USP—United States Pharmacopoeia; HCl—Hydrochloric Acid; Since allfive strengths (50 mg, 150 mg, 200 mg, 300 mg and 400 mg) are doseproportional, stability of data of intermediate strengths (150 mg and300 mg) has not been generated.

Observation: From Table 4 and Table 5, stability data for assay anddissolution shows that:

-   -   the assay of the drug was within the acceptable specification        limits of 90.0%-110.0%,    -   the dissolution values of the stability batches were also within        the acceptable limit of NMT 10% in acid stage and NLT 80% at end        of Buffer stage, and    -   the water content was also NMT 8.0%.

The samples of all the strengths used in the stability studies werefound to be stable for at least for 6 months.

Abbreviations:

-   -   DR: Delayed Release.    -   ER: Extended Release.    -   T/R Ratio: Test/Reference Ratio    -   Intra-subject CV: Intra-subject Coefficient of Variation    -   AUC: Area under the plasma concentration-time curve    -   C_(max): Maximum plasma concentration.    -   NLT: Not less than.    -   NMT: Not more than.    -   BLQ—below limit of quantification.    -   USP—United States Pharmacopoeia.

1. An extended release multi-particulate sprinkle dosage form comprisinga plurality of discrete units, wherein each unit comprises: a) a drugcore comprising quetiapine or a pharmaceutically acceptable saltthereof; b) at least two coatings on the drug core wherein one of the atleast two coatings comprises a pH sensitive polymer; and wherein therelease of the drug is controlled by a combination of said at least twocoatings.
 2. The extended release multi-particulate sprinkle dosage formaccording to claim 1, wherein out of the two coatings surrounding thecore, at least one coating is an extended release coating and the othercoating is a delayed release coating.
 3. The extended releasemulti-particulate sprinkle dosage form according to claim 2, wherein theextended release coating comprises a pH neutral polymer in an amount ofabout 50% to about 80% based on the weight of the enteric coating. 4.The extended release multi-particulate sprinkle dosage form according toclaim 2, wherein the delayed release coating comprises a pH sensitivepolymer in an amount of about 55% to about 95% based on the weight ofthe delayed-release coating.
 5. The extended release multi-particulatesprinkle dosage form according to claim 1, wherein out of the twocoatings surrounding the core, at least one coating comprises a pHneutral polymer or a pH sensitive polymer.
 6. The extended releasemulti-particulate sprinkle dosage form according to claim 1, wherein thetwo coatings may optionally comprise a combination of a pH sensitive andpH neutral polymer.
 7. The extended release multi-particulate sprinkledosage form according to claim 1 wherein the drug core is devoid of anyrelease controlling polymer.
 8. The extended release multi-particulatesprinkle dosage form according to claim 1, wherein the coating mayfurther comprise an optional non-function coating.
 9. The extendedrelease multi-particulate sprinkle dosage form according to claim 1,wherein the dosage form is a sustained or controlled release dosageform.
 10. The extended release multi-particulate sprinkle dosage formaccording to claim 1, wherein the dosage form is a delayed or modifiedrelease dosage form.
 11. The extended release multi-particulate sprinkledosage form according to claim 1, wherein said composition furthercomprises pharmaceutically acceptable excipients selected from adiluent, a binder, a disintegrant, a pore-former, a lubricant, aglidant, a surfactant, a sweetener, an anti-tacking agent, an opacifier,an anti-foaming agent, a coloring agent, a flavoring agent, or a mixturethereof.
 12. The extended release multi-particulate sprinkle dosage formaccording to claim 1, wherein the drug release from the multiparticulatedosage form is controlled with a combination of at least one pH neutralpolymer in a pH neutral coating and at least one pH sensitive polymer ina pH sensitive coating.
 13. The extended release multi-particulatesprinkle dosage form according claim 1, wherein the dosage form is inthe form of a sachet, pouch or capsule.
 14. The extended releasemulti-particulate sprinkle dosage form according to claim 1, wherein atleast one of the discrete units is a form selected from a pellet, abead, a particle, a granule or a mini-tablet.
 15. The extended releasemulti-particulate sprinkle dosage form according to claim 1, wherein thepH neutral polymer is a water-insoluble polymer.
 16. The extendedrelease multi-particulate sprinkle dosage form according to claim 1,wherein the dosage form further comprises a pore former, wherein theratio of the pH neutral polymer and the pore former is 80:20 to 95:5.17. The extended release multi-particulate sprinkle dosage formaccording to claim 1, wherein D50 of at least one of said discrete unitsis in a range of about 0.7 to 1.3 mm or particle size of the discreteunits is less than about 1.6 mm.
 18. The extended releasemulti-particulate sprinkle dosage form according to claim 1, whereinsaid dosage form when administered orally as a single dose with high fatmeals results in not more than a 35% change in Cmax or AUC when comparedto a similar dosing under fasting condition.
 19. The extended releasemulti-particulate sprinkle dosage form according to claim 1, wherein theadministration of the sprinkle dosage form under fasting conditionsprovides a Cmax in range of about 180 ng/mL to about 450 ng/mL and/or amean AUC0-inf in the range of 4000 hr·ng/mL to 4800 hr·ng/mL.
 20. Theextended release multi-particulate sprinkle dosage form according toclaim 1, wherein the administration of the sprinkle dosage form underfed conditions provides a Cmax in range of about 250 ng/mL to about 650ng/mL and/or a mean AUC0-inf in the range of 4300 hr·ng/mL to 6300hr·ng/mL.
 21. The extended release multi-particulate sprinkle dosageaccording to claim 1, wherein said multi-particulate sprinkle dosageform releases not more than 30% of quetiapine when measured in a UnitedStates Pharmacopeia (USP) type I dissolution apparatus, 200 rpm, at atemperature of 37° C.±0.5° C. in 1000 mL of pH 6.60 phosphate bufferfollow on media (after 2 hours dissolution in 0.1 NHCl) after 1st hourof buffer stage.
 22. An extended release multi-particulate sprinkledosage form comprising a plurality of discrete units, wherein saidmulti-particulate sprinkle dosage form releases about 40% to about 70%of quetiapine when measured in a United States Pharmacopeia (USP) type Idissolution apparatus, 200 rpm, at a temperature of 37° C.±0.5° C. in1000 mL of pH 6.60 phosphate buffer follow on media (after 2 hoursdissolution in 0.1 NHCl) after 6th hour of buffer stage.
 23. An extendedrelease multi-particulate sprinkle dosage form comprising a plurality ofdiscrete units, wherein said multi-particulate sprinkle dosage formcomprise coated discrete units having a particle size in the range of0.5 mm-1.6 mm, wherein the discrete units when exposed to water for 60minutes in a syringe, and then passed through a 12 French nasogastrictube into a dissolution medium of 0.1N HCl, releases not more than 0.5%of quetiapine N-oxide impurity after 2 hours, when placed in 1000 mL of0.1N HCl at 100 rpm in USP apparatus I.
 24. The extended releasemulti-particulate sprinkle dosage form according to claim 1 wherein, ahigher amount of quetiapine in a dose range of 50-400 mg can beadministered as a sprinkle dosage form for nasogastric administration,wherein the dosage form can be administered to a patient suffering froma psychiatric disorder selected from schizophrenia, bipolar disorder,mania, depression where patients are unconscious or having swallowingdifficulty.
 25. A method for treating a patient suffering from apsychotic disorders selected from schizophrenia, bipolar disorder,mania, or depression, or as an adjunctive therapy with anantidepressant, by administering a therapeutically effective amount of amulti-particulate quetiapine sprinkle dosage form according to claim 1.26. An extended release multi-particulate sprinkle dosage form preparedby a process comprising: mixing quetiapine or its pharmaceuticallyacceptable salt with suitable excipients and at least two coatings on adrug core wherein one of the at least two coatings comprises a pHsensitive polymer; and wherein the release of the drug is controlled bya combination of the at least two coatings.
 27. The method of claim 26,wherein said process comprises: i. mixing quetiapine or a pharmaceuticalacceptable salt thereof with suitable pharmaceutical acceptableexcipients in a dry mix followed by granulation using a suitabletechnique; ii. extruding the resultant from step i above followed byspheronization; iii. drying the resulting drug containing spheroids; iv.sifting the resultant from step iii above; v. coating the drugcontaining core with suitable coatings; and vi. lubricating the coatedcore followed by filling into a suitable sachet or pouch or capsule. 28.The method of claim 26, wherein said excipient is selected from adiluent, a binder, a disintegrant, a pore-former, a plasticizer, alubricant, a glidant, a surfactant, a sweetener, an anti-tacking agent,an opacifier, an anti-foaming agent, a coloring agent, a flavoring agentor a mixture thereof.